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We studied fibrillin synthesis in cultured fibroblasts from 11 members of a three-generation family with Marfan syndrome, caused by a large in-frame deletion in FBN1 (the fibrillin gene) leading to a loss of 366 bases in the corresponding fibrillin mRNA. Metabolic labelling with [35S]Met/Cys and SDS/PAGE allowed unequivocal identification of normal and truncated fibrillin in all cell strains harbouring the deletion. In culture medium, fibrillin and its truncated counterpart were predominant, whereas their respective larger precursors were found only in traces. This proportion, however, was markedly shifted towards the normal and truncated precursors by EGTA and reversed by the addition of calcium, which confirmed the existence of profibrillin and its probably calcium-dependent conversion into fibrillin. Tunicamycin caused increased electrophoretic mobility of normal and truncated molecules without changing their apparent size differences. Intracellularly, only profibrillin was found; in the mutant cells truncated and normal profibrillin molecules were present in similar amounts and both populations were secreted and deposited simultaneously into the extracellular matrix; there, however, truncated profibrillin only became easily detectable after treatment of cells with dextran sulphate, which increased the amount of extractable profibrillin. Immunofluorescence microscopy in patients' cultures identified fibrillin-containing microfibrils which appeared to be moderately reduced both in amount and diameter. Ultrastructural analysis by rotary-shadowing and immunogold electron microscopy demonstrated the presence of numerous beaded domains reacting with fibrillin antibodies, but no intact fibrillin microfibrils in patient's cell-layer extracts, in contrast with the extensive microfibrils elaborated by control cultures. Our findings suggest, that in the patients' cell cultures all microfibrils contained the truncated fibrillin molecules.

Analyses of truncated fibrillin caused by a 366 bp deletion in the FBN1 gene resulting in Marfan syndrome